It is estimated that there are presently over 2,000,000 regular drug users in this country. Two major classes of drugs, psychostimulants and opiates, comprise the majority of illicit substances used. Compulsive use and abuse of these drugs constitutes a major social and medical problem. The causes underlying drug abuse are complex, involving interactions of social, psychological and biological factors. The goal of neurobiological research is to understand how the brain is affected and changed by these compounds. Although many brain regions may be affected by drug use, particular focus has been given to the nucleus accumbens, a forebrain structure interposed between the limbic system and the motor system. Past research has shown that the nucleus accumbens mediates the reinforcing properties of both stimulants (cocaine and amphetamine) and opiates (heroin and morphine). The current proposal seeks to further examine neurotransmitter interactions and signal transduction mechanisms within the nucleus accumbens, using a behavioral-pharmacological approach in the rat. To accomplish this goal, direct brain microinjection of neurotransmitters or drugs will be employed in conjunction with behavioral paradigms that measure motor activity, responding for conditioned reward, and exploration. There are three major objectives of these experiments: 1) To investigate the role of glutamate-mediated corticolimbic input to the nucleus accumbens in the behavioral effects of psychostimulants and opiates. We will also study the role of glutamate in normal adaptive behavior subserved by the nucleus accumbens, such as exploration and spatial learning. 2) To investigate opiate-dopamine interactions in the nucleus accumbens, focusing particularly on the phenomenon of opiate-induced cross-sensitization to amphetamine and cocaine. 3) To study the role of specific signal transduction mechanisms in behavior mediated by the nucleus accumbens, and how manipulation of such systems may alter the behavioral response to psychostimulants and opiates. For these experiments, intra-accumbens microinjection of bacterial toxins that selectively interfere with G proteins will be carried out in conjunction with studies of motor activity and responding for conditioned reinforcement. Results from this project may contribute to advancement of knowledge in two domains: 1) More detailed understanding of both the behavioral and neurochemical changes induced by psychostimulants and opiates; 2) Further knowledge of the role of specific neural systems within the nucleus accumbens in behavior.